BAK core dimers bind lipids and can be bridged by them

Nat Struct Mol Biol. 2020 Nov;27(11):1024-1031. doi: 10.1038/s41594-020-0494-5. Epub 2020 Sep 14.

Abstract

BAK and BAX are essential mediators of apoptosis that oligomerize in response to death cues, thereby causing permeabilization of the mitochondrial outer membrane. Their transition from quiescent monomers to pore-forming oligomers involves a well-characterized symmetric dimer intermediate. However, no essential secondary interface that can be disrupted by mutagenesis has been identified. Here we describe crystal structures of human BAK core domain (α2-α5) dimers that reveal preferred binding sites for membrane lipids and detergents. The phospholipid headgroup and one acyl chain (sn2) associate with one core dimer while the other acyl chain (sn1) associates with a neighboring core dimer, suggesting a mechanism by which lipids contribute to the oligomerization of BAK. Our data support a model in which, unlike for other pore-forming proteins whose monomers assemble into oligomers primarily through protein-protein interfaces, the membrane itself plays a role in BAK and BAX oligomerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Membrane Lipids / chemistry
  • Membrane Lipids / metabolism*
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Multimerization
  • bcl-2 Homologous Antagonist-Killer Protein / chemistry
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*

Substances

  • BAK1 protein, human
  • Membrane Lipids
  • bcl-2 Homologous Antagonist-Killer Protein